METHOD OF STERILIZATION OF POLYMERIC MATERIALS DEVICES USING HEAT TREATMENT UNDER DRY, SUBSTANTIALLY OXYGEN-FREE INERT GAS AND LOW MOISTURE CONDITIONS

Abstract: This method of sterilization of polymeric medical devices uses a heat treatment which is performed under a substantially oxygen- and moisture-free atmosphere in a chamber thereby preventing extensive thermo-oxydative or hydrolytic degradation.

Description: METHOD OF STERILIZATION OF POLYMERIC MATERIALS DEVICES USING HEAT TREATMENT UNDER DRY, SUBSTANTIALLY OXYGEN-FREE INERT GAS AND LOW MOISTURE CONDITIONS. This invention relates to a method of sterilization of polymeric materials devices using a heat treatment under dry, oxygen-free inert gas or under vacuum. Preferably said polymeric materials devices are produced from bioresorbable or biodegradable polymers. There are basically two prior art methods for sterilization of polymeric medical devices. These are high energy radiation (gamma and/or beta) and so-called gas sterilization using ethylene oxide (ETO) alone or in combination with other gases. Radiation sterilization requires doses in the range of 1.5 to 2.5 Mrad; it is claimed, however, that doses up to 6 Mrad may be necessary to destroy certain micro-organisms. Although this sterilization method is "clean" and effective, it cannot be used with a number of polymers due to their molecular instability upon exposure to radiation. This is especially true with resorbable polymers, although some reports suggest that experimental resorbable internal fixation implants may maintain sufficient mechanical properties, even when degraded during gamma/beta sterilization, especially when they are used in areas of restricted load. However, these suggestions are not well documented and require verification. At present commercial medical devices produced from resorbable polymers are almost exclusively sterilized with ethylene oxide (ETO) . Ethylene oxide sterilization is carried out at temperatures in the range of 21° to 66°C and at a relative humidity of 30 to 60%. Effective gas concentrations are in the range of 400 to 1600 mg/L. ETO is used in its pure form or as 12/88% and/or 20/80% mixtures with carbon dioxide or freon respectively. The drawbacks of ETO sterilization are related to the possibility of by-products formation in the sterilized material (ethylene diol and ethylene chlorohydrin) and to possible chemical reactions between the gas residues present in the sterilized material and tissue proteins. These drawbacks cause an increasing concern about the use of ETO which may eventually be prohibited for sterilization of medical devices. US Patent No. 3 815 315 GLICK discloses e.g. such an ETO sterilization method. The killing of bacterias in this known method is the result of the chemical reaction between the ETO gas and proteins. The purpose of adding of inert gas during ETO sterilization - such as carbon dioxide or freon - is only to reduce the ETO concentration and in consequence enhance the removal of the toxic gas residues from the sterilized products. Therefore the method described by GLICK is not performed under inert gas but an active gas which is ETO. Although GLICK uses anhydrous ETO in order to reduce the high amount of moisture present in the sterilization chamber in ordinary ETO sterilization technique, this amount is still very high, usually in the range of 1 to 5 to 15% relative humidity. The GLICK method is carried out usually at low temperatures at which neither the bacteria nor the spores on the devices would be killed without the action of the toxic ETO. Hence, new and/or modified sterilization methods are required which might replace ETO sterilization. Steam sterilization and heat sterilization as used at present cannot be applied for resorbable polymeric devices as they lead to deformation of the device shape and an extensive hydrolytic and/or thermo-oxidative degradation of the material. The present invention is intended to avoid the drawbacks of both high-energy radiation sterilization and ethylene oxide sterilization used for polymeric medical/devices and especially bioresorbable medical materials/devices. It solves the problem of how to sterilize such devices by applying a heat treatment, preferably a dry-heat treatment in a fashion that sterilizes the devices completely, i.e. not only on the surface but also in the bulk, without causing their thermo-oxidative degradation, plastic deformation and a loss of functionality. In addition the heat-treatment technique of the invention allows for the release of stresses accumulated in the devices, e.g. during the production process, e.g. injection-moulding. In the sterilization method according to the invention the polymeric devices in the sterilization chamber preferably are evacuated repeatedly under high vacuum, and after each evacuation period the chamber is flushed with dry/oxygen-free inert gas and then evacuated again. For the purpose of this invention "oxygen-free" means the exclusion of any form of oxygen either in the diatomic form or in any dissociated or associated form. e.g. ozone or ethylene oxide. The heat-treatment of devices (sterilization) is finally carried out at the predetermined temperature for predetermined time under an inert gas atmosphere or under vacuum. The dry-heat-treated materials/devices are then tested for sterility and possible changes in physical/mechanical properties. It has to be kept in mind that if there is a thermo-oxidative degradation during sterilization the molecular weight of a polymer may decrease. This in consequence might result in a drastic drop in mechanical properties and the loss of device functionality. In addition, there is the potential for increase in material crystallinity and the loss of the chain orientation which is introduced into devices during hot- and/or cold-drawing process. These may affect degradation and maintenance of mechanical properties of a device in vivo which are essential for an adequate performance of the device. In addition, if the temperature used for sterilization is too high, the device may undergo plastic deformation and hence, loose functionally which would exclude its use. On the other hand, if the temperature applied is too low and time used for sterilization too short the bacterial life will be not destroyed which would lead to the device-associated infection. The method according to the invention can be used for sterilization of any polymeric material/device but it is particularly suitable for sterilization of resorbable polymers, providing that the melting temperature of a polymeric material/device to be sterilized is higher than 100°C and preferably higher than 150°C. The additional advantage of the method according to the invention is related to the release of stress concentration in the polymeric medical devices which were produced by melt-processing, e.g. injection-moulding, compression-moulding, extrusion, or by solvent-processing, e.g. solution-casting. At a high concentration of such stresses in the device, a premature failure of the device can be expected when it is implanted due to propagation of cracks formed during an abrupt stress release in the wet in vivo environment. Although the technique described in the present invention can be used with almost any synthetic and many natural polymers such as polya ideε, polyolefines, polyesters, polyethers, polyurethanes, polyether ketones, cellulosics, etc., it is especially suitable for sterilization of resorbable materials/devices from polymers such as polyhydroxyacids, polyorthoesterε, polycarbonates, polyanhydrides, polyesteramides, etc. The crystallinity and the melting temperature of the materials and devices heat-treated according may be increased up to 60% of the initial values as measured by standard methods, e.g. differential scanning colorimetry, density measurements, X-ray measurements, etc. Crystallinity and melting temperature may alternatively be decreased by means of the release of stresses in the material or by decrease of the chain orientation (T m ) , or partial melting in the amorphous and crystalline domains which is not accompanied by recrystallization which leads to the formation of crystals of higher thermodynamic stability. The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming part of this disclosure. For the better understanding of the invention, its operating advantages and specific objects attained by its use, reference should be had to the accompanying drawings, descriptive matter and examples in which are illustrated and described preferred embodiments of the invention. In the drawings: Fig. 1 is a schematic representation of a sterilization chamber which can be used for performing the method according to the invention. Fig. 1 represents a typical sterilization chamber which can be used with the method of the invention. Polymeric devices 1 to be sterilized are placed in a vacuum chamber 2. The valve 3 is closed and the valve 4 opened allowing for evacuation of the system at temperatures in the range of 0° to 300°C under a vacuum in the range of 10 -1 to 10 -10 bar or better. After a defined evacuation time the valve 4 is closed and then the valve 3 is opened allowing for the flow of an inert gas into the chamber which replaces the gas in the chamber. Then the valve 3 is closed and the chamber evacuated again. This procedure is repeated several times. Finally under vacuum and/or under the atmosphere of the inert gas with valves 3 and 4 closed the temperature of the chamber 2 is increased to the predetermined treatment/sterilization temperature and the contents of the chamber 2 maintained at this temperature for the predetermined time necessary for killing the bacterial life on the surface and in the bulk of the polymeric device 1. The duration of the dry-heat treatment of the polymeric materials/devices may be prolonged over the optimal period necessary for sterilization. This will increase the safety margin of the sterilized material/device. Typical time periods for the heat treatment are 15 minutes to 50 hours, and more typically between 1 and 5 hours. Two examples for typical sterilization procedures according to the method of the invention are described below in full detail. Example I: Resorbable pins for fixation of osteochondral defects were produced from poly(L-lactide) by injection-moulding and packed in pouches. The pins were placed in the sterilization/vacuum chamber of the apparatus according to Fig. 1 at room temperature and evacuated to a pressure of 10 -2 bar for 1 hour. Next the vacuum was reduced by filling the chamber with dry, oxygen-free argon and evacuated again under the same conditions. This procedure was repeated 3 times. The third evacuation run was carried out at 70 ° C to enhance the gas mixing/evacuation process. Finally, the chamber was filled with argon, the valves were closed and the temperature in the chamber was increased to 135°C. The pins were maintained at this temperature for a period of time from 30 minutes to 50 hours and cooled down under nitrogen to room temperature. Sterility of the pins on the surface and in the bulk was tested using standard procedures. Mechanical properties (strengths and Young's moduli in shearing and bending mode 4-point bending) were measured and molecular weight was evaluated from GPC (gel permeation chromatography) analysis and viscosity measurements. It has been found that as early as 1 to 5 hours after the dry-heat treatment the pins were sterile. After up to 5 hours of treatment there was a 10% increase in Young's moduli, 10 to 15% increase in the shearing force and 5% drop in flexural strength. There was no change in molecular weight. The dry-heat treatment for 40 to 50 hours resulted in a drop in mechanical properties and molecular weight. From 1 to 4 hours of heat treatment there was 3 - 5 % increase in crystallinity and 2 % decrease in the melting temperature. Treatment for 10 to 40 hours resulted in an increase of crystallinity of 25 % and melting temperature of Example II: Resorbable pins were produced from poly(L/D-lactide) and poly(L/DL-lactide) by injection-moulding and packed in pouches. The pins were placed in the sterilization/vacuum chamber of the apparatus according to Fig. 1 at room temperature and evacuated under vacuum of 10 -2 bar for 1 hour. Next the vacuum was reduced by filling the chamber with dry, oxygen-free argon and evacuated again under the same conditions. This procedure was repeated 3 times. The third evacuation run was carried out at 70"C to enhance the gas mixing/evacuation process. Finally, the chamber was evacuated to 2 x 10 -2 bar, the valves were closed and the temperature in the chamber was increased to 135°C. The pins were maintained at this temperature for a period of time from 30 minutes to 50 hours and cooled down to room temperature. Sterility of the pins on the surface and in the bulk was tested using standard procedures. Mechanical properties (strengths and Young's moduli in shearing and bending mode-4-point bending) were measured and molecular weight was evaluated from GPC (gel permeation chromatography) analysis. It has been found that as early as 1 to 5 hours after the dry-heat treatment the pins were sterile. Up to 20 hours of treatment there was a 50 % increase in Youngs' moduli, no change in the shearing force and 10 % drop in flexural strength for poly(L/D-lactide) and for poly(L/DL-lactide) after 5 hours of dry-heat treatment there was 17 % increase in Youngs' moduli, no change in the shearing force and 12 % drop in flexural strength. For both polymers the dry-heat treatment led to the increase in crystallinity in the range of 15 to 30 % and in melting temperature in the range of 2 to 5 %. There was no change in molecular weight. The dry-heat treatment for 30 to 50 hours resulted in a drop in mechanical properties and molecular weight. Example III: Resorbable pins made from poly(L-lactide) were dry heat treated under vacuum for 2 hours. They showed an increase in molecular weight from 250.000 to 310.000, improving the mechanical properties of the pins. Example IV: Resorbable pins produced from poly(L/DL-lactide) 70/30% were dry heat treated in an oxygen-free atmosphere for 5 hours; there was no change in molecular weight over the exposure period. Example V: Resorbable pins produced from poly(L/DL-lactide) 50/50% with a molecular weight of 300.000 were dry heat treated in an oxygen-free atmosphere for 10 hours; there was a gradual decrease of molecular weight to 290.000 not affecting the mechanical functionality of the pins.

Claims: Claims 1. Method of sterilization by heat treatment of a device made of a polymeric material having a melting peak temperature, characterized in that the method comprises the steps of: a) placing the device in a chamber; b) providing a substantially oxygen- and moisture-free atmosphere in the chamber; c) elevating the temperature in the chamber to a predetermined temperature below the melting peak temperature of the polymeric material and between 71°C to 300°C; and d) maintaining the elevated temperature and said oxygen- and moisture-free atmosphere for a predetermined time. 2. Method according to claim 1, characterized in that said heat treatment is performed at temperatures in the range of 100°C to 300°C, preferably of 110°C - 150°C. 3. Method according to claim 1, characterized in that before elevating the temperature, the device is surrounded with dry, substantially oxygen-free inert gas. 4. Method according to one of the claims 1 - 3, characterized in that said heat treatment is performed under vacuum, preferably in the pressure range of 10 —1 to 10—in υ bar. 5. Method according to one of the claims 1 - 4, characterized in that said heat treatment is performed in an atmosphere having less than 100'000 ppm oxygen, preferably less than 10 ppm oxygen. 6. Method according to one of the claims 1 - 5, characterized in that the temperature in the chamber is elevated without the addition of moisture to the chamber. 7. Method according to one of hte claims 1 - 6, characterized in that the moisture in the chamber is reduced to an maintinaed at less than 100'000 ppm moisture, preferably less than 10 ppm moisture. 8. Method according to one of the claims 1 - 7, characterized in that said heat treatment is performed for at least 5 minutes, preferably for at least 60 minutes. 9. Method according to one of the claims 1 - 8, characterized in that the polymeric material has a melting temperature range and wherein the predetermined temperature in the chamber is elevated to a temperature below the melting range of the polymeric material. 10. Method according to one of the claims 1 - 9, characterized in that the polymeric material is a semi-crystalline polymer and the predetermined temperature in the chamber is between 1 to 300°C below the peak temperature of the polymer. 11. Method according to one of the claims 1 - 9, characterized in that the polymeric material is a non-crystalline polymer and the predetermined temperature in the chamber is between 1 to 300°C below the flowing temperature of the polymer. 12. Method according to one of hte claims 1 -11, characterized in that the predetermined temperature is between 115° - 160°, preferably between 125 ° - 135 ° . 13. Method according to one of the claims 1 - 12, characterized in that it further includes repeatedly flushing the chamber with an inert gas and subsequently evacuating the chamber and elevating the temperature in the chamber to a predtermined temperature. 14. Method according to one of the claims 1 - 13, characterized in that the polymeric material is a bioresorbable or biodegradable material. 15. Method according to one of the claims 1 - 14, characterized in that the polymeric material has a melting peak temperature above 100°C, preferably above 150°C. 16. Method of sterilizing a polymeric material and devices made from the polymeric material in an environment of dry-heat and in an inert gas atmosphere or under vacuum, the temperature and time of treatment being selected so that the crystallinity and melting temperature of the polymeric material or device remains essentially unchanged from before sterilization. 17. Method of sterilizing a polymeric material and devices made from the polymeric material in an environment of dry-heat and in an inert gas atmosphere or under vacuum, the temperature and time of treatment being selected so that the crystallinity and melting temperature of the polymeric material or device are increased up to 60% of the initial values. 18. Method of sterilizing a polymeric material and devices made from the polymeric material in an environment of dry-heat and in an inert gas atmosphere or under vacuum, the temperature and time of treatment being selected so that the crystallinity and melting temperature of the polymeric material or device are decreased. 19. Method of sterilizing a polymeric material and devices made from the polymeric material in an environment of dry-heat and in an inert gas atmosphere or under vacuum, the temperature and time of treatment being selected so that the molecular weight of the polymeric material or device remains unchanged. 20. Method of sterilizing a polymeric material and devices made from the polymeric material in an environment of dry-heat and in an inert gas atmosphere or under vacuum, the temperature and time of treatment being selected so that the molecular weight of the polymeric material or device is increased. 21. Method of sterilizing a polymeric material and devices made from the polymeric material in an environment of dry-heat and in an inert gas atmosphere or under vacuum, the temperature and time of treatment being selected so that the molecular weight of the polymeric material or device is decreased. 22. Method of sterilizing a polymeric material and devices made from the polymeric material in an environment of dry-heat and in an inert gas atmosphere or under vacuum, the temperature and time of treatment being selected so that polydispersity of the polymeric material or device remains unchanged. 23. Method of sterilizing a polymeric material and devices made from the polymeric material in an environment of dry-heat and in an inert gas atmosphere or under vacuum, the temperature and time of treatment being selected so that polydispersity of the polymeric material or device is increased. 24. Method of sterilizing a polymeric material and devices made from the polymeric material in an environment of dry-heat and in an inert gas atmosphere or under vacuum, the temperature and time of treatment being selected so that polydispersity of the polymeric material or device is decreased.

Inventors: GOGOLEWSKI SYLWESTER, PERREN STEPHAN M, GOGOLEWSKI, SYLWESTER, PERREN, STEPHAN, M.
Applicants: AO FORSCHUNGSINST, GOGOLEWSKI SYLWESTER, PERREN STEPHAN M, AO-FORSCHUNGSINSTITUT DAVOS, GOGOLEWSKI, SYLWESTER, PERREN, STEPHAN, M.
Application year: 1994
Main classification: A61L2
IPC codes: A61L2